HU190589B - Process for preparing acid additional salts of 4-chloro-phenoxy-acetic acid-1,3-bis/dimethyl-amino/-2-propyl-ester - Google Patents

Abstract

This invention relates to the new 1,3-bis-(dimethylamino)-2-propyl-4-chlorophenoxyacetate of the Formula (I) <IMAGE> (I) acid addition salts thereof, a process for the preparation of the same and pharmaceutical compositions comprising the said compounds. The novel compound of the present invention corresponds to the Formula (I). This compound stimulates the function of the brain cells and thereby mental activity. The compound of the Formula (I) can be prepared by esterifying (4-chlorophenoxy)-acetic acid or a functional reactive derivative thereof with 1,3-bis-(dimethylamino)-2-propanol or a halogeno derivative thereof in a manner known per se.

Description

The present invention relates to a process for the preparation of acid addition salts of a compound of formula (I) by reacting a compound of formula (II)

R ¹ is carboxyl, cyano, alkoxycarbonyl, 4-chlorophenoxyacetyloxycarbonyl, halocarbonyl, or -COOMe ¹ wherein Me ^{1 is} an alkali metal or ammonium ion ( III) - in which formula

R ² is hydroxyl ceopor, or a halogen atom is reacted using any of the ester-forming reactions and the resulting

4-Chloro-phenoxy-acetic acid 1,3-bis (diroethylamino) -2-propyl ester is recovered from the reaction mixture, preferably in the form of its hydrochloric acid salt.

It is known that 4-chlorophenoxyacetic acid-2-dimethylaminoethyl ester is a drug-containing drug, centrophenoxin, which is well-established as a central stimulant in medicine. (Arzneimittel Forsch. 13 881 (1963))

Experiments on the mechanism of action of this compound have shown that the substance originally known as neuroenergetics also influences the cellular aging process. In fact, the use of centrophenoxin has been shown to reduce the aging pigment content of brain neurons and myocardium in chronic animals (Naturre 210 313/1966 /, significantly prolongs the age of experimental animals and improves the learning ability of old animals). Expl. Gerontol. 8, 185 (1973b)

According to the membrane hypothesis of cellular aging, the first step in the aging of post-mitotic cells is a decrease in the passive potassium permeability of the cell membrane, probably due to the cross-linking effect of aggressive free radicals produced during cellular respiration. (J. Theor. Bioi. 75 189 (1978), Mech. Age. Dev. 9 237 (1979)). In the case of centrophenoxin, the in vitro sustained incorporation of diroethylaminoethanol from the drug into brain tissue has a significant neutralizing effect on free radicals, probably related to the electron-release capacity of the nitrogen atom in the molecule. (Mech. Age. Dev. 14,245 (1980))

Nitrogen-containing 4-chlorophenoxyacetic acid esters known in the art, like centrophenoxin, contain a substituted amino group. (Bull. Soc. Chim. Francé, 1960 1786, Bioi. Active. Soedin, 1965 112, C.A. 63 17948c / 1965)

It is envisaged that by doubling the wavelength of the diroethylamino groups it will be possible to produce a molecule more efficient than centrophenoxin, which may be capable of pharmacologically influencing the cellular aging process.

In our work, the doubling of the substituted amino groups was accomplished by the preparation of 1,3-bis (dimethylamino) -2-propyl ester of 4-chlorophenoxyacetic acid.

Ester formation can be carried out using any of the methods known in the art. (S. Patai: The Chemistry of Carboxylic Acids and Esters. Wiley, London, 1969). The product may be obtained, for example, by reaction of the free acid and alcohol with dicyclohexylcarbodiimide, or by reacting the acid with its halogen (nitrile, anhydride) and alcohol, or with the halide of the reactant in an organic solvent. medium.

Thus, ester formation can be accomplished by reacting 4-chlorophenoxyacetic acid chloride (nitrile, anhydride, etc.) with 1,3-bis (dimethylamino) -2-propanol for 2-3 hours. The reaction is carried out under stirring at 60-80 ° C in a solution of the reactants in an organic solvent (e.g. benzene, toluene, xylene). The ester formed is conveniently recovered as its hydrochloric acid salt and purified by recrystallization.

The acute toxicity values of the compound were determined in male CFLP albino mice by intraperitoneal and oral administration.

Intraperitoneally, increments of 600 mg / kg incremental increments of 50 mg / kg were administered to 5 to 3 3-month-old mice per dose. The maximum dose was 800 mg / kg. After 72 years, the LDso value determined by the Lichtfield - Wilcoxon graphical method is i.p. administration was 700 ± 42 µg / kg.

Per os dosing in saline solution from 1800 mg / kg in steps of 400 mg / kg up to a maximum dose of 3400 mg / kg in 5 to 5 mice at 1.5 months of age. After 72 hours, the results were evaluated orally. The LD 50 value was 2540 at 300 mg / kg.

The biological activity of 4-chlorophenoxyacetic acid-1,3-bis-dimethylamino) -2-propyl ester was investigated in terms of survival in chronic treatment, receiving 5 CFY rats in 100 mg / kg saline daily i.p. Using the compound of the invention, the mean age of the animals was prolonged by about 5 months compared to the control group.

Examining the effect of the new ester derivative produced on biological membranes, we have found that microviscosity of membranes of synaptosomes isolated from the cortex, as measured by diphenylhexetriene fluorescence anisotropy, increases significantly with age. 20 days 100 mg / kg i.p. treatment with snow spores in CFY rats resulted in a significant improvement in this parameter when values dropped to levels almost 1 year of age. This result is fully consistent with the increase in average age.

The effect of the new ester object of the invention on brain RNA synthesis in Old rats (24 months) was found, whereas in control animals total and m RNA synthesis of cortical cells slows down to about half of that seen in young and adult animals. at 4 weeks of 100 mg / kg ip treatment, the rate of synthesis of both RNA fractions is significantly accelerated and almost returns to that seen in 1-year-old adult animals.

Based on these results, it is expected that 4-chlorophenoxyacetic acid 1,3-bis (dimethylamino) -2-propyl ester can enhance brain cell function and related intellectual activity (including associative and learning ability). ) in conditions where they have reduced functional capacity due to either the natural aging process, organic diseases or traumatic conditions, or possibly narcosis. Thus, its use as a neurostimulant and as a prophylactic .antiaging agent prior to the development of cerebral dysfunction may be significant.

The pharmacological use of a compound of the invention may be accomplished by:

p.os .: The active ingredient, alone or in admixture with solid excipients (starch, cellulose, talc), is known to form tablets, dragees, capsules, etc. in the form of.

i.in aqueous venous solution or in a physically inert organic solvent (various glycols).

i.muscular solution as i.v. formulation or suspension.

Amount of active ingredient in different formulations:

In solid dosage form: 20-90%

Solution: 1-10%

In suspension: 1-70%

Further details of the process are set forth in the following examples, without limiting the invention thereto.

Example 1

13.0 g (0.063 mol) of 4-chlorophenoxyacetic acid chloride are dissolved in 140 ml of benzene. The solution was cooled to 0 ° C and 18.52 g (0.126 mol) of 1,3-bis (dimethylamino) -2-propanol was added dropwise with stirring so that the temperature did not rise to 10 ° C. After the dropwise addition, the reaction mixture was refluxed for 3 hours, and the solvent was evaporated in vacuo. The remaining 4-chlorophenoxyacetic acid-1,3-bis (dimethylamino) -2-propyl ester was dissolved in diethyl ether-acetone (10: 1) and the hydrochloric acid salt was separated off with hydrochloric acid gas. The crude product was filtered, washed with ether and recrystallized from isopropyl alcohol.

Yield: 21.0 g (85.5%) Mp: 210-12 ° C Elemental analysis for C15H23CIN2OJ.2HCl (387.7):

Found: C, 46.46; H, 6.50; N, 7.22; Cl, 27.43; Found: C 45.42 H 6.56 N 7.70 Cl 28.26% λ max. (methanol) 276 nm logc 1.5104 IR (KBr): 2580 (amine-BOR), 1765 (estercarbonyl) 1215, 1080 (arylalkyl ether), 820 (aromatic p-position) cm -1 ¹ H NMR (DMSO): δ 7.23-7.17 (m, aromatic), δ 5.71 (s, CH), δ 5.20 (s, OCH2), δ 3.47 (s, CH2). ), 4 2.90 (s, CH 2);

Example 2

6.5 g (0.032 mol) of 4-chlorophenoxyacetic acid chloride are dissolved in 120 ml of toluene. The solution was cooled to 0 ° C and 9.4 g (0.064 mol) of 1,3-bis (dimethylamino) -2-propanol was added dropwise below 10 ° C. The reaction mixture was maintained at 80-82 ° C for 3 hours, then cooled to room temperature and quenched with 4-k] h-phenoxyacetic acid 1,3-bis (dimethylamino) -2-propyl ester with hydrochloric acid. salt.

The crude product is filtered off, washed with isopropyl alcohol and recrystallized from isopropyl alcohol.

Yield: 10.1 g (82.2%) Mp: 209-11 ° C The final product identification test results were in accordance with the values given in the first example.

Example 3

4-Chlorophenoxyacetic anhydride (6.0 g, 0.017 mol) was dissolved in benzene (70 ml) and 1,3-bis (dimethylamino) (5.6 g, 0.019 mol) was added dropwise with stirring at 5-10 ° C. 2-Propanol The reaction mixture was refluxed for 3 hours and then the solvent was evaporated in vacuo. The residual 4-chlorophenoxy-acetic acid-1,3-bis (dimethylamino) -2-propyl ester was dissolved in diethyl ether-acetone (10: 1) and the hydrochloric acid salt was removed with boric acid gas. The crude product was filtered off and recrystallized from isopropyl alcohol.

Yield: 5.7 g (87.02%) M.p .: 209-11 ° C

The test results for the final product identification were the same as in the first example.

Example 4

15.0 g (0.085 mol) of 4-chlorophenoxyacetic acid nitrile are dissolved in 80 ml of toluene. 14.7 g (0.1 mol) of 1,3-bis (dimethylamino) -2-propanol and 2.0 ml of 85% sulfuric acid are added at 5-10 ° C. The reaction mixture was refluxed for 4-5 hours, then cooled to room temperature and neutralized with sodium carbonate solution. The neutral solvent phase is washed with water and dried, and the hydrochloric acid salt of 4-chlorophenoxyacetic acid-1,3-bis (dimethylamino) -2-propyl ester is separated off. The crude product was filtered, dried and recrystallized from isopropyl alcohol. Yield: 25.67 g (78.2%) M.p .: 208-10 ° C

The test results for the final product identification were the same as in the first example.

Example 5

18.66 g (0.1 mol) of 4-chlorophenoxyacetic acid are dissolved in 40 ml of isopropyl alcohol. A solution of 16.70 g (0.1 mol) of 1,3-bis (dimethylamino) -2-chloropropane in isopropyl alcohol is added dropwise with stirring at 5-10 ° C. The reaction mixture was heated at reflux for 2 hours, cooled, diethyl ether (200 mL) was added and the hydrochloride salt of 4-chlorophenoxyacetic acid-1,3-bis (dimethylaraino) -2-propyl ester was removed with hydrochloric acid gas. The product was filtered and washed with ether.

Yield: 31.2 g (80.5%) Mp: 208-10 ° C

The test results for the final product identification were the same as in the first example.

Example 6

Sodium salt of 4-chlorophenoxyacetic acid (20.86 g, 0.1 mol) was dissolved in dimethylformamide (40 ml).

It is added dropwise at 5-10 ° C

A solution of 16.7 g (0.1 mol) of 1,3-bis (dimethylamino) -2-chloropropane in isopropyl alcohol. The reaction mixture was refluxed for 2 hours, cooled and, after adding 200 ml of diethyl ether, the hydrochloride salt of 4-chlorophenoxyacetic acid-1,3-bis (dimethylamino) -2-propyl ester was removed with hydrogen chloride gas.

Yield: 30.62 g (85%) M.p .: 208-11 ° C

The test results for the final product identification were the same as in the first example.

Example 7

10.0 g (0.05 mol) of methyl 4-chlorophenoxyacetic acid, 7.35 g (0.05 mol) of 1,3-bis (dimethyl: 1-amino) -2-propanol and Sodium ethylate (9 g) in benzene (30 ml) was heated at reflux for 10 hours and the resulting methanol, in the form of an azeotropic mixture of benzene, was continuously distilled off from the reaction mixture. The resulting solution was distilled in vacuo, and the residue was dissolved in diethyl ether-acetone (10: 1) and the hydrochloride salt of 4-chlorophenoxyacetic acid-1,3-bis (2-dimethylamino-2-propyl ester) was separated. . The crude product is filtered off and recrystallized from isopropyl alcohol.

Yield: 14.80 g (76.5%) Mp: 207-10 ° C

The test results for the final product identification are the same as in the first example.

Example 8

250 mg tablets:

composition per tablet:

agent 250 mg lactose 45 mg Krist. cellulose 17 mg talc 5 rags paraffin oil 8 mg 2500 g of crystalline active substance, 450 g anhydrous lactose, 170 g anhydrous crystalline in a cellulose homogenizer homogenized with 80 g of paraffin oil and 350 g to be water with isopropyl alcohol. thereafter the mass filter, sift through a sieve and the granules

oven dried. The dried material is homogenized with 50 g of talc and pressed into a 325 mg tablet in a conventional tabletting machine.

Example 9

Enteric solvent capsules or dragees:

The product described in the previous example is provided with an enteric coating in a manner known per se 10. example

Capsule:

Per unit dosage: active ingredient: 250 mg qu.s .: known excipients

Depending on the size of the batch, the active ingredient is homogenized with the pre-mixed excipients and filled into hard gelatine capsules in a suitable device.

-4190589

Example 11

250-500 mg powder for ampoules:

Composition per ampoule:

250 mg of active substance / powder

500 mg active ingredient / powder ampoule Solution for ampoule:

aqua des. pro inj. 10 tnl / ampoule

Claims (4)

PATENT 1CENNA POINTS A process for the preparation of acid addition salts of a compound of formula (I) comprising the steps of: - in which formula R 'is carboxy], cyano, alkoxycarbonyl, 4-chlorophenoxyacetyloxycarbonyl, or halocarbonyl with a compound of formula III - in which formula R ² represents hydroxyl group, or a halogen atom is reacted with any of the esterification reactions application to those, and the resulting 4-chlorophenoxy acetic acid, 1,3-bis dimethylamino) -2-propyl ester acid addition salt - preferably in the form hydrochloride salt recovering the reaction mixture. (Priority: May 2, 1983) 2. A process for the preparation of acid addition salts of a compound of formula (I) comprising: II. a compound of formula wherein R 'is -COOMe' wherein Me 'is an alkali metal or ammonium ion and a compound of formula III wherein R ² represents a halogen atom is reacted. (Priority: 11.11.1985) 3. A process according to claim I wherein the 4-chlorophenoxyacetic acid chloride is reacted with 1,3-bis (dimethylamino) -2-propanol. (Priority: May 2, 1983) A process for the preparation of a pharmaceutical composition, wherein the 4-chloro-phenoxyacetic acid 1,3-bis (dimethylamino) -2-propyl ester produced by the process of claim 1 is optionally one or more known, pharmaceutically acceptable. in combination with excipients - fencing, flavoring, preserving, thickening, emulsifying, antioxidant, 20 buffers, lubricants - pills, capsules, dragees, tablets, suppositories, inj. solution, suspension, emulsion, etc. in a manner known per se to form a pharmaceutical composition. (Priority: May 2, 1983) 5. A process for the preparation of a pharmaceutical composition, wherein the 4-chlorophenoxyacetic acid 1,3-bis (dimethylamino) -2-propyl ester produced by the process of claim 2 is optionally more known in the art. 30) g in combination with acceptable excipients - carrier, flavoring, preserving, thickening, emulsifying agents, antioxidants, buffers, lubricants - pills, capsules, dragees, tablets, suppositories, inj. solution, suspension, 35 emulsions etc. in a manner known per se to form a pharmaceutical composition. (Priority: 11.11.1985)